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Michael D. Hogarty, MD

Attending Physician

Associate Professor of Pediatrics, Perelman School of Medicine at the University of Pennsylvania

I’m a pediatric oncologist with both clinical and research responsibilities. On the clinical side, I have developed expertise in the management of patients with neuroblastoma, germ cell tumors, and histiocytic diseases (such as Langerhans cell histiocytosis and hemophagocytic lymphohistiocytosis, or LCH and HLH). I help coordinate the care of children with these diseases at Children's Hospital, and have roles in the international community in developing clinical and translational programs for neuroblastoma and histiocytic diseases. This involves leadership roles within the Children’s Oncology Group (COG), the International Neuroblastoma Risk Group (INRG), and the International Histiocyte Society.

In the laboratory, I'm involved in neuroblastoma research, an interest initially developed while training with Dr. Garrett Brodeur here at Children’s Hospital. Dr. Brodeur is a world renowned researcher studying the molecular pathogenesis of this tumor. He piqued my interest in neuroblastoma and I continue to study it even after transitioning to my own independent laboratory. My lab currently focuses on defining the cancer pathways that support neuroblastoma development, particularly those that interact with the MYCN gene, and in developing novel therapeutics that might target this disease.

Neuroblasts are the immature cells that will eventually develop into the adrenal glands and peripheral nerve tissues of a child. When these cells fail to mature properly, they may instead become cancerous -- giving rise to neuroblastoma. My laboratory studies the behavior of such neuroblastoma cells, what distinguishes them from their normal counterparts, and what facets of their behavior might be exploited by novel treatments. Surprisingly, many of the genetic changes that occur in cancer cells to make them very aggressive also provide certain vulnerabilities that can be exploited once they are understood.

Currently, we have several major laboratory projects underway. First, we are studying how MYC genes regulate polyamines, and how amplification of the MYCN gene (which is found in about 25 percent of tumors and is associated with a very aggressive tumor) causes a tumor to be dependent on polyamines. We’ve discovered that numerous medications that interfere with steps in the pathway of making polyamines can disrupt neuroblastomas -- either blocking them before they form, or making tumors regress or respond more fully to standard therapies. These novel approaches have been validated in complementary models of neuroblastoma in mice and will also be studied in children with relapsed high-risk disease.

We also are studying the process by which neuroblastoma cells become resistant to the body’s protective mechanisms to prevent them from becoming cancerous, and ultimately how these cells become resistant to the chemotherapy and radiation therapy used to kill them. A large part of this process is overseen by proteins of the Bcl2 family. Our laboratory has been defining the patterns of Bcl2 proteins that cause poor treatment response. We’ve also been studying diverse small molecule drugs that interfere with those functions of the Bcl2 family that keep cancer cells alive. These studies are designed to both improve the initial response of these tumors to chemotherapy, and also to restore therapy responses in tumors cells that have become resistant and relapsed.

These two areas of study have been rewarding because not only do they help us better understand the biology underlying this cancer type and its distinct behaviors, but because each of these areas is leading directly into new therapies. We anticipate that drugs in both of these classes will soon be tested in clinical trials to see if they improve the outcome of children with advanced neuroblastoma.

One of the things that makes our neuroblastoma program at Children's Hospital unique is the depth and breath of our team – from basic research to the translation of novel discoveries to new therapies that improve outcomes. We have the ability to translate the gap from bedside to bench and provide the most effective treatments now and for the future.
 

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